Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells

Junli Chang, Hongshen Wang, Xianyang Wang, Yongjian Zhao, Dongfeng Zhao, Chenglong Wang, Yimian Li, Zhilie Yang, Sheng Lu, Qinghua Zeng, Jacquelyn Zimmerman, Qi Shi, Yongjun Wang, Yanping Yang

Research output: Contribution to journalArticle

Abstract

Osteosarcoma is a most common highly malignant bone tumor in children and adolescents. Polyphyllin I (PPI) is an ethanol extraction from Paris polyphylla Smith var.yunnanensis (Franch.) Hand.-Mazz, which belongs to antipyretic-detoxicate family and has been used as a natural medicine in the treatment of infectious disease and cancer in China for centuries. The proteasome activity inhibitory and anti-osteosarcoma effects of PPI have not been known. Here we found PPI exhibited a selective inhibitory effect on proteasomal chymotrypsin (CT)-like activity, both in purified human proteasome and in cultured osteosarcoma cellular proteasome, and caused an accumulation of ubiquitinated proteins. PPI also inhibited viability, proliferation, migration, and invasion of MG-63, Saos-2, and U-2 OS osteosarcoma cells and resulted in S phase arrest and apoptosis. Furthermore, we explored the molecular targets involved. Exposure of osteosarcoma cells to PPI caused an inactivation of the intrinsic nuclear factor κB (NF-κB) and activation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress signaling cascade in osteosarcoma cells, followed by down-regulation of anti-apoptotic proteins, with up-regulation of pro-apoptotic proteins. We also demonstrated down-regulation of c-Myc, Cyclin B1, Cyclin D1, and CDK1, which are involved in the cell cycle and growth. Finally, we identified down-regulation of Vimentin, Snail, Slug, and up-regulation of E-cadherin, which are integral proteins involved in epithelial-mesenchymal transition (EMT). Taken together, our data provide insights into the mechanism underlying the anticancer activity of PPI in human osteosarcoma cells.

Original languageEnglish (US)
Pages (from-to)117-127
Number of pages11
JournalJournal of Ethnopharmacology
Volume170
DOIs
StatePublished - May 30 2015

Keywords

  • Apoptosis
  • Cell cycle
  • Epithelialmesenchymal transition
  • Osteosarcoma
  • Polyphyllin I
  • Proteasome activity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells'. Together they form a unique fingerprint.

  • Cite this

    Chang, J., Wang, H., Wang, X., Zhao, Y., Zhao, D., Wang, C., Li, Y., Yang, Z., Lu, S., Zeng, Q., Zimmerman, J., Shi, Q., Wang, Y., & Yang, Y. (2015). Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells. Journal of Ethnopharmacology, 170, 117-127. https://doi.org/10.1016/j.jep.2015.05.006